Health by design; optimising our urban environmental microbiomes for human health.

Humans have evolved in direct and intimate contact with their environment and the microbes that it contains, over a period of 2 million years. As a result, human physiology has become intrinsically linked to environmental microbiota. Urbanisation has reduced our exposure to harmful pathogens, however there is now increasing evidence that these same health-protective improvements in our environment may also be contributing to a hidden disease burden: immune dysregulation. Thoughtful and purposeful design has the potential to ameliorate these health concerns by providing sources of microbial diversity for human exposure. In this narrative review, we highlight the role of environmental microbiota in human health and provide insights into how we can optimise human health through well-designed cities, urban landscapes and buildings. The World Health Organization recommends there should be at least one public green space of least 0.5 hectare in size within 300m of a place of residence. We argue that these larger green spaces are more likely to permit functioning ecosystems that deliver ecosystem services, including the provision of diverse aerobiomes. Urban planning must consider the conservation and addition of large public green spaces, while landscape design needs to consider how to maximise environmental, social and public health outcomes, which may include rewilding. Landscape designers need to consider how people use these spaces, and how to optimise utilisation, including for those who may experience challenges in access (e.g. those living with disabilities, people in residential care). There are also opportunities to improve health via building design that improves access to diverse environmental microbiota. Considerations include having windows that open, indoor plants, and the relationship between function, form and organisation. We emphasise possibilities for re-introducing potentially health-giving microbial exposures into urban environments, particularly where the benefits of exposure to biodiverse environments may have been lost.

Extreme events, trophic chain reactions, and shifts in phenotypic selection.

Demographic consequences of rapid environmental change and extreme climatic events (ECEs) can cascade across trophic levels with evolutionary implications that have rarely been explored. Here, we show how an ECE in high Arctic Svalbard triggered a trophic chain reaction, directly or indirectly affecting the demography of both overwintering and migratory vertebrates, ultimately inducing a shift in density-dependent phenotypic selection in migratory geese. A record-breaking rain-on-snow event and ice-locked pastures led to reindeer mass starvation and a population crash, followed by a period of low mortality and population recovery. This caused lagged, long-lasting reductions in reindeer carrion numbers and resultant low abundances of Arctic foxes, a scavenger on reindeer and predator of migratory birds. The associated decrease in Arctic fox predation of goose offspring allowed for a rapid increase in barnacle goose densities. As expected according to r- and K-selection theory, the goose body condition (affecting reproduction and post-fledging survival) maximising Malthusian fitness increased with this shift in population density. Thus, the winter ECE acting on reindeer and their scavenger, the Arctic fox, indirectly selected for higher body condition in migratory geese. This high Arctic study provides rare empirical evidence of links between ECEs, community dynamics and evolution, with implications for our understanding of indirect eco-evolutionary impacts of global change.

Consequences of cross-season demographic correlations for population viability.

Demographic correlations are pervasive in wildlife populations and can represent important secondary drivers of population growth. Empirical evidence suggests that correlations are in general positive for long-lived species, but little is known about the degree of variation among spatially segregated populations of the same species in relation to environmental conditions. We assessed the relative importance of two cross-season correlations in survival and productivity, for three Atlantic puffin (Fratercula arctica) populations with contrasting population trajectories and non-overlapping year-round distributions. The two correlations reflected either a relationship between adult survival prior to breeding on productivity, or a relationship between productivity and adult survival the subsequent year. Demographic rates and their correlations were estimated with an integrated population model, and their respective contributions to variation in population growth were calculated using a transient-life table response experiment. For all three populations, demographic correlations were positive at both time lags, although their strength differed. Given the different year-round distributions of these populations, this variation in the strength population-level demographic correlations points to environmental conditions as an important driver of demographic variation through life-history constraints. Consequently, the contributions of variances and correlations in demographic rates to population growth rates differed among puffin populations, which has implications for-particularly small-populations' viability under environmental change as positive correlations tend to reduce the stochastic population growth rate.

Raising offspring increases ageing: Differences in senescence among three populations of a long-lived seabird, the Atlantic puffin.

Actuarial senescence, the decline of survival with age, is well documented in the wild. Rates of senescence vary widely between taxa, to some extent also between sexes, with the fastest life histories showing the highest rates of senescence. Few studies have investigated differences in senescence among populations of the same species, although such variation is expected from population-level differences in environmental conditions, leading to differences in vital rates and thus life histories. We predict that, within species, populations differing in productivity (suggesting different paces of life) should experience different rates of senescence, but with little or no sexual difference in senescence within populations of monogamous, monomorphic species where the sexes share breeding duties. We compared rates of actuarial senescence among three contrasting populations of the Atlantic puffin Fratercula arctica. The dataset comprised 31 years (1990-2020) of parallel capture-mark-recapture data from three breeding colonies, Isle of May (North Sea), Røst (Norwegian Sea) and Hornøya (Barents Sea), showing contrasting productivities (i.e. annual breeding success) and population trends. We used time elapsed since first capture as a proxy for bird age, and productivity and the winter North Atlantic Oscillation Index (wNAO) as proxies for the environmental conditions experienced by the populations within and outside the breeding season, respectively. In accordance with our predictions, we found that senescence rates differed among the study populations, with no evidence for sexual differences. There was no evidence for an effect of wNAO, but the population with the lowest productivity, Røst, showed the lowest rate of senescence. As a consequence, the negative effect of senescence on the population growth rate (λ) was up to 3-5 times smaller on Røst (Δλ = -0.009) than on the two other colonies. Our findings suggest that environmentally induced differences in senescence rates among populations of a species should be accounted for when predicting effects of climate variation and change on species persistence. There is thus a need for more detailed information on how both actuarial and reproductive senescence influence vital rates of populations of the same species, calling for large-scale comparative studies.

Influence of health-system change on treatment burden: a systematic review.

BACKGROUND: Treatment burden is a patient-centred concept describing the effort required of people to look after their health and the impact this has on their functioning and wellbeing. High treatment burden is more likely for people with multiple long-term conditions (LTCs). Validated treatment burden measures exist, but have not been widely used in practice or as research outcomes. AIM: To establish whether changes in organisation and delivery of health systems and services improve aspects contributing to treatment burden for people with multiple LTCs. DESIGN AND SETTING: Systematic review of randomised controlled trials (RCTs) investigating the impact of system-level interventions on at least one outcome relevant to previously defined treatment burden domains among adults with ≥2 LTCs. METHOD: The Embase, Ovid MEDLINE, and Web of Science electronic databases were searched for terms related to multimorbidity, system-level change, and treatment burden published between January 2010 and July 2021. Treatment burden domains were derived from validated measures and qualitative literature. Synthesis without meta-analysis (SWiM) methodology was used to synthesise results and study quality was assessed using the Cochrane risk-of-bias (version 2) tool. RESULTS: The searches identified 1881 articles, 18 of which met the review inclusion criteria. Outcomes were grouped into seven domains. There was some evidence for the effect of system-level interventions on some domains, but the studies exhibited substantial heterogeneity, limiting the synthesis of results. Some concern over bias gave low confidence in study results. CONCLUSION: System-level interventions may affect some treatment burden domains. However, adoption of a standardised outcome set, incorporating validated treatment burden measures, and the development of standard definitions for care processes in future research would aid study comparability.

Forest management affects seasonal source-sink dynamics in a territorial, group-living bird.

The persistence of wildlife populations is under threat as a consequence of human activities, which are degrading natural ecosystems. Commercial forestry is the greatest threat to biodiversity in boreal forests. Forestry practices have degraded most available habitat, threatening the persistence of natural populations. Understanding population responses is, therefore, critical for their conservation. Population viability analyses are effective tools to predict population persistence under forestry management. However, quantifying the mechanisms driving population responses is complex as population dynamics vary temporally and spatially. Metapopulation dynamics are governed by local dynamics and spatial factors, potentially mediating the impacts of forestry e.g., through dispersal. Here, we performed a seasonal, spatially explicit population viability analysis, using long-term data from a group-living territorial bird (Siberian jay, Perisoreus infaustus). We quantified the effects of forest management on metapopulation dynamics, via forest type-specific demography and spatially explicit dispersal, and how forestry impacted the stability of metapopulation dynamics. Forestry reduced metapopulation growth and stability, through negative effects on reproduction and survival. Territories in higher quality natural forest contributed more to metapopulation dynamics than managed forests, largely through demographic processes rather than dispersal. Metapopulation dynamics in managed forest were also less resilient to disturbances and consequently, may be more vulnerable to environmental change. Seasonal differences in source-sink dynamics observed in managed forest, but not natural forests, were caused by associated seasonal differences in dispersal. As shown here, capturing seasonal source-sink dynamics allows us to predict population persistence under human disturbance and to provide targeted conservation recommendations.

Improving the health assistant in nursing employment model through entry to practice nursing student perceptions: a cross-sectional study.

Background: A model employing entry to practice nursing students as health assistants in nursing (HANs) was developed to support the nursing workforce.Objective: This research examines the perceived benefits of being employed as a HAN to graduate entry to practice nursing students.Design: Cross-sectional studyMethods: A web-based 33-item questionnaire was open to entry to practice nursing students employed as a HAN. Categorical measures were summarised using descriptive statistics. Qualitative comments were analysed thematically.Results: Of the 39 enrolled participants, 38 (97.4%) completed the study. Fifteen students (39.5%) commenced a graduate year in 2019, 12 (31.6%) commenced a graduate year in 2020 and 11 (28.9%) will commence a graduate year in 2021. The participants viewed HAN employment as an opportunity to further develop as nurses and suggested that the HAN scope of practice expand to include their existing nursing scope of practice, thereby optimising their learning experience.Conclusion: The HAN model is viewed as a valuable model of employment by entry to practice nursing students; however, the HAN scope of practice is viewed as too limited and not conducive to self-development. This may impact on the retention of HAN employees as they transition to registered graduate nurse employment.Impact statement: Graduate entry to practice nursing students offer direction on how to improve the Health Assistants in Nursing employment model.

Pericytes on placental capillaries in terminal villi preferentially cover endothelial junctions in regions furthest away from the trophoblast.

INTRODUCTION: Pericytes are a common feature in the placental microvasculature but their roles are not well understood. Pericytes may provide physical or endocrine support for endothelium and in some tissues mediate vasoconstriction. METHODS: This study uses serial block-face scanning electron microscopy (SBFSEM) to generate three-dimensional (3D) reconstructions of placental pericytes of the terminal villi and transmission electron microscopy (TEM) to study pericyte endothelial cell interactions. The proportion of endothelial cell junctions covered by pericytes was determined. RESULTS: The detailed 3D models of placental pericytes show pericyte structure at a new level of detail. Placental pericytes have many fingers extending from the cell body which can span multiple capillary branches. The proportion of endothelial cell-cell junctions covered by pericytes was significantly higher than pericyte coverage of capillary endothelium as a whole (endothelium: 14%, junctions: 43%, p < 0.0001). However, the proportion of endothelial cell-cell junctions covered by pericytes in regions adjacent to trophoblast was reduced compared to regions >3 µm away from trophoblast (27% vs 62% respectively, p < 0.001). No junctional complexes were observed connecting pericytes and endothelial cells but there were regions of cell membrane with features suggestive of intercellular adhesions. DISCUSSION: These data suggest that the localisation of pericytes on the villous capillary is not random but organised in relation to both endothelial junctions and the location of adjacent trophoblast. This further suggests that pericyte coverage may favour capillary permeability in regions that are most important for exchange, but limit capillary permeability in other regions.

Environmental change reduces body condition, but not population growth, in a high-arctic herbivore.

Environmental change influences fitness-related traits and demographic rates, which in herbivores are often linked to resource-driven variation in body condition. Coupled body condition-demographic responses may therefore be important for herbivore population dynamics in fluctuating environments, such as the Arctic. We applied a transient Life-Table Response Experiment ('transient-LTRE') to demographic data from Svalbard barnacle geese (Branta leucopsis), to quantify their population-dynamic responses to changes in body mass. We partitioned contributions from direct and delayed demographic and body condition-mediated processes to variation in population growth. Declines in body condition (1980-2017), which positively affected reproduction and fledgling survival, had negligible consequences for population growth. Instead, population growth rates were largely reproduction-driven, in part through positive responses to rapidly advancing spring phenology. The virtual lack of body condition-mediated effects indicates that herbivore population dynamics may be more resilient to changing body condition than previously expected, with implications for their persistence under environmental change.

High-Arctic family planning: earlier spring onset advances age at first reproduction in barnacle geese.

Quantifying how key life-history traits respond to climatic change is fundamental in understanding and predicting long-term population prospects. Age at first reproduction (AFR), which affects fitness and population dynamics, may be influenced by environmental stochasticity but has rarely been directly linked to climate change. Here, we use a case study from the highly seasonal and stochastic environment in High-Arctic Svalbard, with strong temporal trends in breeding conditions, to test whether rapid climate warming may induce changes in AFR in barnacle geese, Branta leucopsis. Using long-term mark-recapture and reproductive data (1991-2017), we developed a multi-event model to estimate individual AFR (i.e. when goslings are produced). The annual probability of reproducing for the first time was negatively affected by population density but only for 2 year olds, the earliest age of maturity. Furthermore, advanced spring onset (SO) positively influenced the probability of reproducing and even more strongly the probability of reproducing for the first time. Thus, because climate warming has advanced SO by two weeks, this likely led to an earlier AFR by more than doubling the probability of reproducing at 2 years of age. This may, in turn, impact important life-history trade-offs and long-term population trajectories.

Contrasting consequences of climate change for migratory geese: Predation, density dependence and carryover effects offset benefits of high-arctic warming.

Climate change is most rapid in the Arctic, posing both benefits and challenges for migratory herbivores. However, population-dynamic responses to climate change are generally difficult to predict, due to concurrent changes in other trophic levels. Migratory species are also exposed to contrasting climate trends and density regimes over the annual cycle. Thus, determining how climate change impacts their population dynamics requires an understanding of how weather directly or indirectly (through trophic interactions and carryover effects) affects reproduction and survival across migratory stages, while accounting for density dependence. Here, we analyse the overall implications of climate change for a local non-hunted population of high-arctic Svalbard barnacle geese, Branta leucopsis, using 28 years of individual-based data. By identifying the main drivers of reproductive stages (egg production, hatching and fledging) and age-specific survival rates, we quantify their impact on population growth. Recent climate change in Svalbard enhanced egg production and hatching success through positive effects of advanced spring onset (snow melt) and warmer summers (i.e. earlier vegetation green-up) respectively. Contrastingly, there was a strong temporal decline in fledging probability due to increased local abundance of the Arctic fox, the main predator. While weather during the non-breeding season influenced geese through a positive effect of temperature (UK wintering grounds) on adult survival and a positive carryover effect of rainfall (spring stopover site in Norway) on egg production, these covariates showed no temporal trends. However, density-dependent effects occurred throughout the annual cycle, and the steadily increasing total flyway population size caused negative trends in overwinter survival and carryover effects on egg production. The combination of density-dependent processes and direct and indirect climate change effects across life history stages appeared to stabilize local population size. Our study emphasizes the need for holistic approaches when studying population-dynamic responses to global change in migratory species.

Evaluating Effectiveness of an Acute Rehabilitation Program in Hospital-Associated Deconditioning.

BACKGROUND AND PURPOSE: Acute hospitalization can result in significant decline in functional ability, known as hospital-associated deconditioning. Older adults are most vulnerable, with resultant functional difficulties and increased risk of institutionalization. This study evaluates the effectiveness of a multidisciplinary acute rehabilitation program in hospital-associated deconditioning on routinely collected outcome data to examine its impact to determine whether a controlled trial is warranted. METHODS: We conducted a retrospective review of the hospital database for the national rehabilitation clinical registry for 2013 and 2014. We analyzed responses from patient feedback questionnaires over a 2-year period to assess patient experience of the rehabilitation program. RESULTS AND DISCUSSION: The analysis included 289 patients referred to our acute rehabilitation program. Most patients were aged 81-90 years, representing 47% (n = 137) of all admissions. The main impairment group was deconditioning (54%). The median entry time to the acute rehabilitation program for this impairment group was 5 days from admission and length of stay in the rehabilitation program was 9 days. Many of these patients (57%) were directly discharged home, with only 21% needing transfer for inpatient rehabilitation. The average Functional Independence Measure score gain was 22 for the patients directly discharged home, with an average discharge Functional Independence Measure score of 94/126. Of the patient feedback responses received (response rate: 24%), 96% rated the program as very good or good. We observed improved functional outcomes among program participants, with the majority directly discharged home, reduced transfer to rehabilitation hospitals, and patient acceptance of this acute rehabilitation program. CONCLUSION: These promising results suggest that a more rigorous evaluation of this acute rehabilitation program in the management of hospital-associated deconditioning is warranted.

Density-dependent population dynamics of a high Arctic capital breeder, the barnacle goose.

Density regulation of the population growth rate occurs through negative feedbacks on underlying vital rates, in response to increasing population size. Here, we examine in a capital breeder how vital rates of different life-history stages, their elasticities and population growth rates are affected by changes in population size. We developed an integrated population model for a local population of Svalbard barnacle geese, Branta leucopsis, using counts, reproductive data and individual-based mark-recapture data (1990-2017) to model age class-specific survival, reproduction and number of individuals. Based on these estimates, we quantified the changes in demographic structure and the effect of population size on age class-specific vital rates and elasticities, as well as the population growth rate. Local density regulation at the breeding grounds acted to reduce population growth through negative effects on reproduction; however, population size could not explain substantial variation in survival rates, although there was some support for density-dependent first-year survival. With the use of prospective perturbation analysis of the density-dependent projection matrix, we show that the elasticities to different vital rates changed as population size increased. As population size approached carrying capacity, the influence of reproductive rates and early-life survival on the population growth rate was reduced, whereas the influence of adult survival increased. A retrospective perturbation analysis revealed that density dependence resulted in a positive contribution of reproductive rates, and a negative contribution of the numbers of individuals in the adult age class, to the realised population growth rate. The patterns of density dependence in this population of barnacle geese were different from those recorded in income breeding birds, where density regulation mainly occurs through an effect on early-life survival. This indicates that the population dynamics of capital breeders, such as the barnacle goose, are likely to be more reproduction-driven than is the case for income breeders.

The interacting effects of forestry and climate change on the demography of a group-living bird population.

Anthropogenic degradation of natural habitats is a global driver of wildlife population declines. Local population responses to such environmental perturbations are generally well understood, but in socially structured populations, interactions between environmental and social factors may influence population responses. Thus, understanding how habitat degradation affects the dynamics of these populations requires simultaneous consideration of social and environmental mechanisms underlying demographic responses. Here we investigated the effect of habitat degradation through commercial forestry on spatiotemporal dynamics of a group-living bird, the Siberian jay, Perisoreus infaustus, in boreal forests of northern Sweden. We assessed the interacting effects of forestry, climate and population density on stage-specific, seasonal life-history rates and population dynamics, using long-term, individual-based demographic data from 70 territories in natural and managed forests. Stage-specific survival and reproductive rates, and consequently population growth, were lower in managed forests than in natural forests. Population growth was most sensitive to breeder survival and was more sensitive to early dispersing juveniles than those delaying dispersal. Forestry decreased population growth in managed forests by reducing reproductive success and breeder survival. Increased snow depth improved winter survival, and warmer spring temperatures enhanced reproductive success, particularly in natural forests. Population growth was stable in natural forests but it was declining in managed forests, and this difference accelerated under forecasted climate scenarios. Thus, climatic change could exacerbate the rate of forestry-induced population decline through reduced snow cover in our study species, and in other species with similar life-history characteristics and habitat requirements.

Upper limb motor training using a Saebo™ orthosis is feasible for increasing task-specific practice in hospital after stroke.

BACKGROUND/AIM: Assistive technologies have the potential to increase the amount of movement practice provided during inpatient stroke rehabilitation. The primary aim of this study was to investigate the feasibility of using the Saebo-Flex™ device in a subacute stroke setting to increase task-specific practice for people with little or no active hand movement. The secondary aim was to collect preliminary data comparing hand/upper limb function between a control group that received usual rehabilitation and an intervention group that used, in addition, the Saebo-Flex™ device. METHODS: Nine inpatients (mean three months (median six weeks) post-stroke) participated in this feasibility study conducted in an Australian rehabilitation setting, using a randomised pre-test and post-test design with concealed allocation and blinded outcome assessment. In addition to usual rehabilitation, the intervention group received eight weeks of daily motor training using the Saebo-Flex™ device. The control group received usual rehabilitation (task-specific motor training) only. Participants were assessed at baseline (pre-randomisation) and at the end of the eight-week study period. Feasibility was assessed with respect to ease of recruitment, application of the device, compliance with the treatment programme and safety. Secondary outcome measures included the Motor Assessment Scale (upper limb items), Box and Block Test, grip strength and the Stroke Impact Scale. RESULTS: Recruitment to the study was very slow because of the low number of patients with little or no active hand movement. Otherwise, the study was feasible in terms of being able to apply the Saebo-Flex™ device and compliance with the treatment programme. There were no adverse events, and a greater amount of upper limb rehabilitation was provided to the intervention group. While there were trends in favour of the intervention group, particularly for dexterity, no between-group differences were seen for any of the secondary outcomes. CONCLUSIONS: This pilot feasibility study showed that the use of assistive technology, specifically the Saebo-Flex™ device, could be successfully used in a sample of stroke patients with little or no active hand movement. However, recruitment to the trial was very slow. The use of the Saebo-FlexTM device had variable results on outcomes, with some positive trends seen in hand function, particularly dexterity.

Increasing the survival of dendritic cells in vivo does not replace the requirement for CD4+ T cell help during primary CD8+ T cell responses.

The survival of dendritic cells (DC) in vivo determines the duration of Ag presentation and is critical in determining the strength and magnitude of the resulting T cell response. We used a mouse model to show that Ag-loaded C57BL/6 DC (MHC class II(+/+) (MHC II(+/+))) that reach the lymph node survived longer than Ag-loaded MHC II(-/-) DC, with the numbers of C57BL/6 DC being approximately 2.5-fold the number of the MHC II(-/-) DC by day 4 and approximately 5-fold by day 7. The differential survival of DC in vivo was not affected by low doses of LPS, but in vitro pretreatment with CD40L or with high doses of LPS increased the numbers of MHC II(-/-) DC to levels approaching those of C57BL/6 DC. Regardless of their numbers and relative survival in lymph nodes, MHC II(-/-) DC were profoundly defective in their ability to induce CTL responses against the gp33 peptide epitope, and were unable to induce expansion and optimal cytotoxic activity of CD8(+) T cells specific for the male Ag UTY. We conclude that CD4(+) T cell help for CD8(+) responses involves mechanisms other than the increased survival of Ag-presenting DC in the lymph node.

Long-term deposition of inhaled antigen in lung resident CD11b-CD11c+ cells.

In this study we report the characterization of a population of lung resident CD11b(-)CD11c(+) cells that are able to take up inhaled antigen and retain it for extended periods of time. Ovalbumin conjugated to fluorescein-isothiocyanate (FITC-OVA) administered intranasally to mice was taken up by two main populations of cells in the lung, a migratory CD11c(+)CD11b(+) population consisting of dendritic cells (DC), which rapidly transported antigen to the draining lymph node (LN), and a resident CD11b(-)CD11c(+) population that retained engulfed antigen without apparently degrading it for up to 8 wk after administration. The FITC(+)CD11b(-)CD11c(+) cells did not migrate to draining LN at a detectable rate, and did not up-regulate expression of costimulatory molecules in response to LPS treatment. FITC(+)CD11b(-)CD11c(+) cells were found in the lung and bronchoalveolar lavage fluid, and their distribution was compatible with macrophages. Although FITC(+)CD11b(-)CD11c(+) cells expressed the DC marker DEC205 and other molecules associated with antigen-presenting cell function, they did not induce proliferation of antigen-specific CD4(+) T cells in vitro or acute cytokine production by activated CD4(+) T cells in vivo. Thus, FITC(+)CD11b(-)CD11c(+) cells appear to represent an intermediate cell type sharing properties with DC and macrophages. These cells may have a role in modulating the responses of lung resident T cells to inhaled antigens.

5,6-Dimethylxanthenone-4-acetic acid treatment of a non-immunogenic tumour does not synergize with active or passive CD8+ T-cell immunotherapy.

The chemotherapeutic drug 5,6-dimethylxanthenone-4-acetic acid (DMXAA) inhibits intratumoural blood flow, causing hypoxia, haemorrhagic necrosis, vascular collapse and tumour cell death. Production of TNF-alpha and IFN is also induced, causing local inflammation and activation of immune cells including CD8+ T cells. We used the tumour cell line LL-LCMV, which expresses the gp33 epitope of lymphocytic choriomeningitis virus in a non-immunogenic form, to investigate whether tumour cell death caused by treatment with DMXAA may improve the success of tumour immunotherapy mediated by CD8+ T cells. Treatment with DMXAA was effective at reducing the size of LL-LCMV tumours. However, compared to normal mice, tumour reduction was no more marked or sustained in mice carrying high numbers of naive, tumour-specific CD8+ T cells. The antitumour effect of activated CD8+ T cells was also not affected by DMXAA treatment. Tumour-specific CD8+ T cells activated in vivo by immunization with dendritic cells and specific tumour peptide antigen, or generated in vitro and adoptively transferred into tumour-bearing mice by i.v. injection, did not improve or sustain the reduction in tumour size induced by DMXAA treatment. We conclude that the presence of high numbers of naive CD8+ T cells, or immunotherapies leading to CD8+ T-cell activation, do not synergize with the tumour cell death and local inflammation induced by DMXAA treatment. It is possible that this lack of synergism may result from both treatments inducing activation of CD8+ T cells and that treatments that activate different populations of immune cells may achieve better success.